Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks (original) (raw)

Hyaluronic acid (HA) is one of nature's most versatile and fascinating macromolecules. Being an essential component of the natural extracellular matrix (ECM), HA plays an important role in a variety of biological processes. Inherently biocompatible, biodegradable and non-immunogenic, HA is an attractive starting material for the construction of hydrogels with desired morphology, stiffness and bioactivity. While the interconnected network extends to the macroscopic level in HA bulk gels, HA hydrogel particles (HGPs, microgels or nanogels) confine the network to microscopic dimensions. Taking advantage of various scaffold fabrication techniques, HA hydrogels with complex architecture, unique anisotropy, tunable viscoelasticity and desired biologic outcomes have been synthesized and characterized. Physical entrapment and covalent integration of hydrogel particles in a secondary HA network give rise to hybrid networks that are hierarchically structured and mechanically robust, capable of mediating cellular activities through the spatial and temporal presentation of biological cues. This review highlights recent efforts in converting a naturally occurring polysaccharide to drug releasing hydrogel particles, and finally, complex and instructive macroscopic networks. HA-based hydrogels are promising materials for tissue repair and regeneration. body by hyaluronidase and reactive oxygen species, with tissue half-lives ranging from minutes in the blood to hours or days in skin and joints. 6 HA is an attractive building block for the fabrication of artificial matrices for tissue engineering because it is biocompatible, biodegradable, bioactive, non-immunogenic and non-thrombogenic. 7 In physiological solutions, HA assumes an expanded random coil structure that occupies a very large domain that facilitates solute diffusion. Although high molecular weight HA at high concentrations in solution (e.g. 5 MDa at >0.1 mg/mL) can form entangled molecular networks that are viscoelastic, solutions of HA do not have long lasting mechanical integrity. To afford HA-based hydrogels with tailored mechanical properties and degradation rates, while at the same time maintaining their native biological functions, controlled chemical modification and covalent crosslinking are often necessary. By varying the molecular weight of HA, the degree of modification and the concentration of the reactive HA precursors, hydrogels with varying stiffness, pore size and degradation rate can be readily produced. Additional biological functionality can be incorporated into HA gels via the coupling of different biological moieties, cytokines and therapeutic drugs. Efficient, biocompatible and chemo-selective crosslinking chemistries have enabled the encapsulation of cells during gelation, giving rise to three dimensional (3D) cell/gel constructs with intimate cell-matrix interactions. 10